This project is a continuation of a grant from 1999 where we were funded to begin analyses of the genotypings of primarily late-onset Alzheimer's disease (AD) families with affected relative pairs using microsatellite markers at a 10 cM resolution as part of a complete genome-wide search for AD genes. The analyses of 1524 affected and unaffected relative pairs from 457 AD families has just been completed. Seventeen candidate regions of interest (CRI) were identified on chromosomes 1, 3-6, 9-12, 14, 15, and 19-21 from the analyses of the whole dataset and various sub-groups. Also part of the grant's aims was to follow-up CRI with flanking microsatellite markers to a -5 cM resolution to confirm the CRI and begin family-based association testing of polymorphisms in candidate genes located in these CRI. Candidate genes should fit into the model of inflammatory or oxidative damage pathways and/or are related to AD production that are believed to be key to the pathogenesis of Alzheimer's disease. Follow-up confirmatory analyses of these CRI are almost complete for most of the above chromosomes. We have begun investigation of several candidate genes in some of these CRI and have reported associations of polymorphisms in the tumor necrosis factor (TN F) gene in a candidate gene subset and a cohort of African-American AD patients and controls. We also have preliminary data indicating an association of the TNF receptor 1 gene, located in a CR1 on chromosome 1, to Alzheimer's disease. In this present proposal, we will finish confirmatory follow-up analyses of the 11 CR1 and continue genotyping polymorphisms in candidate genes for family-based association testing. Our Specific Aims are:1) Continue follow-up of those individuals with blood for change in status and autopsy, 2) Complete follow-up confirmatory analyses of other Candidate Regions of Interests (CR1) found in the genome scan by genotyping flanking markers and performing genetic analysis, 3) Continue pursuit of AD candidate genes within the confirmed CRIs, known to be involved either in amyloid or tangle processing, inflammation, an/or reactive oxygen species (ROS) generation or depletion. 4) Genotype and analyze newly hypothesized AD candidate genes identified from the literature through consultation with Dr Tanzi's laboratory at MGH.